US10350274B2 - Method for the preparation of human albumin with reduced level of dissolved oxygen - Google Patents

Method for the preparation of human albumin with reduced level of dissolved oxygen Download PDF

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US10350274B2
US10350274B2 US14/724,649 US201514724649A US10350274B2 US 10350274 B2 US10350274 B2 US 10350274B2 US 201514724649 A US201514724649 A US 201514724649A US 10350274 B2 US10350274 B2 US 10350274B2
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albumin
solution
stage
dissolved oxygen
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US20170000855A9 (en
US20150343025A1 (en
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Juan Ignacio Jorquera Nieto
Ana Maria Ortiz Fernandez
Montserrat Costa Rierola
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Grifols SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • C07K14/765—Serum albumin, e.g. HSA
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method for the preparation of a solution of human albumin, more particularly it relates to a method comprising a stage of reducing the dissolved oxygen in said solution of albumin until a concentration equal to or less than 0.5 ppm.
  • a solution of human albumin having a redox state closer to the redox state of the albumin present in human plasma.
  • a method of preparing a solution of a human albumin includes a stage of reducing a level of dissolved oxygen in the solution, wherein the level of dissolved oxygen is reduced to a concentration equal to or less than 0.5 ppm.
  • the stage of reducing the level of dissolved oxygen in the solution can be carried out by a surface treatment of the solution with an inert gas or by bubbling of an inert gas into an interior of the solution.
  • the human albumin can be of any origin, such as a plasmatic recombinant origin or a transgenic origin.
  • An exemplary concentration of the human albumin would be between about 4% and 25% (w/v).
  • Examples of the inert gas include nitrogen or helium.
  • the stage of reducing the level of dissolved oxygen in the solution is sometimes carried out prior to or subsequent to a stage of pasteurisation of the solution.
  • the solution can be maintained in an inert gas atmosphere, including a gas such as nitrogen or helium, subsequent to the stage of reducing the level of dissolved oxygen in the solution.
  • a gas such as nitrogen or helium
  • the solution can be packed and/or stored in a container including a material impermeable to oxygen, such as glass.
  • An exemplary concentration of dissolved oxygen would be equal to or less than 0.5 ppm.
  • the solution can be prepared into a medicament.
  • FIG. 1 shows a schematic diagram of a method for the obtainment of therapeutic human albumin from plasma utilised in the prior state of the art.
  • Human albumin is a non-glycosylated protein of 66 kDa. Quantitatively, it is the most significant plasma protein and the concentration thereof in normal plasma lies between 35 and 50 g/l, constituting up to 60% of total plasmatic proteins (Peters T. J.: All About Albumin; Biochemistry, Genetics and Medical Applications. Academic Press, San Diego, 1996).
  • human albumin consists of a polypeptide having 585 amino acids with about 67% alpha-helices, without beta-sheets being present (Otagiri M., Chuang V. T.: Pharmaceutically important pre- and posttranslational modifications on human serum albumin. Biol Pharm Bull 2009; 32:527-534).
  • Human albumin contains methionine and 35 cysteine residues involved in the formation of 17 disulphide bonds. Cys-34 is the only free cysteine in the entire molecule.
  • Human albumin has specific antioxidant functions by virtue of the capacity to bond to multiple ligands and the radical entrapment properties thereof, both closely related to the structure thereof.
  • Cys-34 is a site particularly sensitive to oxidation/reduction. Consequently, in general, it is legitimate to speak of the redox state of albumin in terms of Cys-34.
  • chromatographic separation of albumin three fractions are obtained, according to the redox state of Cys-34 (Peters, 1996, op. cit.):
  • Albumin may undergo diverse structural modifications, both in vivo and during the methods employed to produce therapeutic albumin, resulting in the modification of the conformation thereof and, as a consequence, the bonding properties together with the redox state thereof (Oettl, K. et al, 2010, op. cit.).
  • the Cohn method commences with human plasma which is subjected to successive stages of precipitation and separation. In each a precipitate enriched in one of the plasmatic proteins and a decantation supernatant is obtained.
  • a precipitate enriched in one of the plasmatic proteins and a decantation supernatant is obtained.
  • parameters of the solution such as, inter alia, pH, dielectric constant, temperature, protein concentration, and ionic strength.
  • said Cohn fractions contain increasing concentrations of ethanol.
  • the albumin contained in the supernatant of Fraction IV is precipitated with about 40% (v/v) ethanol and goes on to form part of the paste of Fraction V.
  • Fraction V is obtained, the latter is resuspended in a solution and is subjected to different stages until the final product is obtained.
  • these stages include: diafiltration, heat treatment, sterilisation, filling into vials, and final pasteurisation of said vials, prior to submission of said vials to quarantine, in general during a period of not less than 14 days at 30-32° C., with the objective of ensuring the sterility of the final product.
  • the inventors have discovered that, by means of the addition of a stage in the process of production of a solution of human albumin comprising reducing the dissolved oxygen in the solution, wherein the level of oxygen is reduced to a concentration equal to or less than 0.5 ppm, a reduction in the oxidation of Cys-34 is achieved, there being obtained a redox state of the albumin very similar to the redox state which albumin presents in blood plasma.
  • a redox state of the albumin very similar to the redox state which albumin presents in blood plasma.
  • the present invention reveals a method for the preparation of a solution of human albumin characterised in that it comprises a stage of reducing the dissolved oxygen in said solution of albumin, wherein the level of oxygen is reduced to a concentration equal to or less than 0.5 ppm.
  • said solution of albumin is maintained in an inert gas atmosphere.
  • Said stage of reducing the dissolved oxygen in the solution of albumin may be carried out in various ways known in the state of the art.
  • a surface treatment of the solution of albumin may be realised with an inert gas or an inert gas may be bubbled into the interior of said solution of albumin.
  • Said inert gas used in the method of the present invention may be nitrogen, helium or similar gases.
  • the method of the present invention may be utilised for the obtainment of solutions of albumin having an albumin concentration of between about 4 and 25% (w/v).
  • the obtained albumin is therapeutic albumin.
  • the albumin of the present invention may be albumin obtained in recombinant or transgenic form.
  • the molecule of recombinant or transgenic albumin is identical to human albumin in terms of the sequence of amino acids thereof, it does not present glycosylation and, having the objective of it being functional, it must present the same conformational folding as the albumin of human plasmatic origin. Should this not be so it could not be administered to humans by virtue of the risk of immunogenicity, among other possible adverse effects caused by said differences.
  • the stage of reducing the dissolved oxygen in the solution of albumin of the present invention may be carried out prior to or subsequent to a stage of pasteurisation of said solution of albumin, or moreover it may be carried out although a stage of pasteurisation of said solution of albumin is not realised, being independent of the process of preparation of the initial solution of albumin.
  • said solution of albumin is maintained in an inert gas atmosphere.
  • Said inert gas atmosphere may be of nitrogen, helium or similar gases.
  • said container is manufactured from a material impermeable to oxygen, more preferably from glass.
  • a further objective of the present invention is to reveal a composition comprising human albumin prepared by means of the method of the present invention and the use thereof as medicament.
  • the present invention reveals the use of a composition comprising albumin prepared according to the hereinbefore described method for the preparation of a medicament.
  • Cohn's Fraction V Human plasma obtained from healthy donors was subjected to successive stages of precipitation and separation, according to Cohn's method (Cohn E. J. et al, 1946, op. cit.), from the obtainment of the initial cryoprecipitation supernatant until achieving the precipitation of Fraction V (see FIG. 1 ).
  • Cohn's Fraction V was suspended in cold water for injection (WFI), it was adjusted to pH 7.0 and was clarified by means of in-depth filters. The clarified solution was diafiltered at constant volume, applying a dialysis solution formed by a salt of monovalent ions (sodium chloride) and maintaining the temperature at 5° C. ( FIG. 1 , clarification/diafiltration stage).
  • Sodium caprylate and N-acetyltryptophan were added as stabilisers to the diafiltered solution.
  • Said solution was subjected to heat treatment at 60° C. ( FIG. 1 , heat-treatment stage).
  • the heat-treated solution was diluted with WFI or was concentrated as a function of the desired final protein concentration desired (for example, 5%, 20% or 25% (w/v)) ( FIG. 1 , non-packed solution).
  • the final solution was then filtered in a sterile manner (0.22 ⁇ m filters) and the filling of the final sterile containers was proceeded to in an aseptic zone ( FIG. 1 , sterile filtration and filling stage).
  • the solution in the final container was heated at 60° C.
  • FIG. 1 pasteurization in vials stage.
  • FIG. 1 pasteurization in vials stage.
  • the vials were incubated at 30-32° C. during not less than 14 days ( FIG. 1 , quarantine stage). Following said period, the vials were visually inspected to discard any indication of microbial contamination ( FIG. 1 , final albumin product).
  • the oxidative state of the samples of albumin from different stages of the process of obtainment of the albumin was analysed by high-performance liquid chromatography (HPLC), based on the method described by Oettl K., 2010, op. cit., and as detailed below.
  • the samples of albumin under study were diluted in a buffer of 0.3 M, sodium chloride, 0.1 M sodium phosphate, pH 6.87, to a concentration of 6.5 mg/ml, and 5 ⁇ l was injected into a Shodex Asahipak ES-502N DEAE anion exchange column (7.5 ⁇ 100 mm, Shodex, Japan) with a flow of 1.0 ml/min.
  • the detection of the three fractions of the albumin as a function of the oxidative state thereof was carried out by means of fluorescence, utilising as excitation and emission wavelengths 280 and 340 nm, respectively.
  • the quantification of the concentration of the HMA, HNA1 and HNA2 forms of Cys-34 of the albumin was carried out taking into account the height of each of the peaks of interest obtained in the corresponding chromatogram.
  • FIG. 2 shows the change in the oxidative state of the samples of human serum albumin from different stages during the process of obtainment of albumin of the prior state of the art.
  • the data shows an increase in the HNA1 and HNA2 forms in detriment to the HMA form, particularly subsequent to the stage of pasteurisation with subsequent quarantine (final 20% albumin product).
  • the behaviour of the oxidative state of the albumin following the stages of pasteurisation and quarantine in purified 5% and 25% albumin concentration from human plasma with the method of the prior state of the art ( FIG. 3 ) is equivalent to that observed for the final 20% albumin products following the same technique ( FIG. 2 ).
  • the data obtained shows an increase in the HNA1 and HNA2 forms in detriment to the HMA form, particularly following the stage of pasteurisation with subsequent quarantine.
  • Example 2 Method for the Obtainment of Albumin of the Present Invention utilising a Stage of Surface Treatment with Nitrogen Prior to the Pasteurisation
  • the method for the obtainment of the albumin of the present invention corresponds to the method described in Example 1, further including a stage of reducing dissolved oxygen in the solution of albumin, as is described below.
  • a surface treatment with nitrogen was carried out, inserting into the chlorobutyl stopper of the vial two hypodermic needles (of the commercial type Braun Sterican 21G ⁇ 11 ⁇ 2′′, 0.80 ⁇ 40 mm, Germany, or similar) connected to two 0.22 ⁇ m PVDF filters (of the commercial type Millex GV Millipore, 0.22 ⁇ m, PVDF, 13 mm filter, USA, or similar), avoiding contact of the needles with the solution of albumin.
  • One of the needles was destined as the inlet of the nitrogen gas and the other as the outlet thereof having the objective of preventing overpressure within the container.
  • the treatment with surface nitrogen was carried out at room temperature for two hours, maintaining a constant flow of nitrogen having the objective of permitting observation of the movement of the liquid within the container without it splashing within the same.
  • Example 1 pasteurization in vials stage
  • FIG. 4 shows the results obtained, there was observed the non-decrease in the HMA form and the non-increase in the HNA1 and HNA2 forms observed in FIGS. 2 and 3 with the method for the obtainment of the albumin of the prior art.
  • the employed probe whose functioning is based on the principle of the galvanic cell, comprised a silver (Ag) anode sheathed with a platinum (Pt) wire functioning as cathode.
  • the aforedescribed assembly is inserted in a protective cover full of an electrolytic solution of potassium chloride which has at its extremity a membrane of Teflon®, a material permeable to the gas, permitting the passage of the oxygen present in the solution but not the passage of the solution itself.
  • a potential of 790 mV the oxygen present in the cell is reduced to hydroxide ions (OH ⁇ ) at the cathode and silver chloride is deposited at the anode.
  • This reaction brings about a current flow having an intensity proportional to the quantity of oxygen present in the sample.
  • the meter then converts the measurement of the current flow into the corresponding concentration of dissolved oxygen.
  • Example 3 Method for the Obtainment of Albumin of the Present Invention utilising a Stage of Bubbling Nitrogen into the Solution Prior to the Pasteurisation
  • the method for the obtainment of the albumin of the present invention corresponds to the method described in Example 1, including the stage described below.
  • the treatment of bubbling nitrogen was carried out by inserting into the chlorobutyl stopper of the vial two hypodermic needles (of the commercial type Braun Sterican 21G ⁇ 11 ⁇ 2′′, 0.80 ⁇ 40 mm, Germany, or similar) connected to two 0.22 ⁇ m PVDF filters (of the commercial type Millex GV Millipore, 0.22 ⁇ m, PVDF, 13 mm filter, USA, or similar).
  • a spinal needle (of the commercial type Terumo Spinal Needle, 18G ⁇ 31 ⁇ 2′′, 1.20 ⁇ 90 mm, Japan, or similar), was submerged in the solution of albumin and the hypodermic needle (of the commercial type Braun Sterican 21G ⁇ 11 ⁇ 2′′, 0.80 ⁇ 40 mm, Germany, or similar), located avoiding contact with the liquid, was destined as the outlet thereof having the objective of preventing overpressure within the container.
  • the treatment of bubbling nitrogen was carried out at room temperature for two hours, maintaining a constant flow of nitrogen having the objective of permitting observation of small bubbles within the liquid.
  • the method for the obtainment of albumin from human plasma continued as described in Example 1 ( FIG. 1 , pasteurization in vials stage), until the obtainment of the final albumin product.
  • the oxidative state was analysed by means of anion exchange chromatography of the samples of 20% albumin concentration obtained by the technique of the present invention. Specifically, samples of albumin subjected to a stage of bubbling nitrogen prior to the stage of pasteurisation, samples of albumin following the pasteurisation and prior to quarantine, and samples of albumin following the period of quarantine, were analysed.
  • FIG. 5 shows the results obtained, these being similar to those obtained in FIG. 4 , utilising a stage of surface treatment with nitrogen prior to the pasteurisation. There was observed the non-decrease in the HMA form and the non-increase in the HNA1 and HNA2 forms observed in FIGS. 2 and 3 with the method for the obtainment of albumin of the prior art.
  • Example 4 Method for the Obtainment of Albumin of the Present Invention utilising a Stage of Surface Treatment with Nitrogen Prior to the Pasteurisation, Applied to Different Final Concentrations of Albumin
  • the method for the obtainment of the albumin of the present invention corresponds to the method described in Example 2, applied to other concentrations of albumin such as 5 and 25%.
  • the oxidative state of the samples of 5 and 25% concentration of albumin obtained with the technique of the present invention was analysed by means of anion exchange chromatography. Specifically, samples of 5 and 25% albumin subjected to a stage of surface treatment with nitrogen prior to the pasteurisation, samples of 5 and 25% albumin subsequent to the pasteurisation and prior to quarantine, and samples of 5 and 25% albumin following the quarantine period, were analysed.
  • FIG. 6 shows the results obtained, these being similar to those obtained in FIG. 4 for albumin at a concentration of 20%. There was observed the non-decrease in the HMA form and the non-increase in the HNA1 and HNA2 forms observed in FIGS. 2 and 3 with the method for the obtainment of the albumin of the prior art.
  • Example 5 Method for the Obtainment of Albumin of the Present Invention utilising a Stage of Surface Treatment with Helium Prior to the Pasteurisation
  • the method for the obtainment of the albumin of the present invention corresponds to the method described in Example 1, including the stage described below.
  • the surface treatment with helium was carried out, inserting into the chlorobutyl stopper, and avoiding contact with the solution of albumin, two hypodermic needles (of the commercial type Braun Sterican 21G ⁇ 11 ⁇ 2′′, 0.80 ⁇ 40 mm, Germany, or similar) connected to two 0.22 ⁇ m PVDF filters (of the commercial type Millex GV Millipore, 0.22 ⁇ m, PVDF, 13 mm filter, USA, or similar), avoiding contact of the needles with the solution of albumin.
  • One of the needles was destined as the inlet of the helium gas and the other as the outlet thereof having the objective of preventing overpressure within the container.
  • the treatment with surface helium was carried out at room temperature for two hours, maintaining a constant flow of helium having the objective of permitting observation of the movement of the liquid within the container without it splashing within the same.
  • the method for the obtainment of albumin commencing from human plasma continued as described in Example 1 ( FIG. 1 , pasteurization in vials stage), until the obtainment of the final albumin product.

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ES2524516B1 (es) * 2014-05-29 2015-03-31 Grifols Worldwide Operations Limited Procedimiento de preparación de albúmina humana con nivel de oxígeno disuelto reducido
EP3995141B1 (en) 2016-04-28 2024-01-03 Alkahest, Inc. Plasma fractions as therapy for thymic cancer
UA126232C2 (uk) 2016-08-18 2022-09-07 Алкахест, Інк. Спосіб лікування когнітивного розладу, пов'язаного зі старінням, та набір, що містить фракцію плазми крові
CA3061194A1 (en) 2017-04-26 2018-11-01 Alkahest, Inc. Dosing regimen for treatment of cognitive and motor impairments with blood plasma and blood plasma products
WO2020018343A1 (en) 2018-07-20 2020-01-23 Alkahest, Inc. Dosing regimen for treatment of cognitive and motor impairments with blood plasma and blood plasma products
CN109627322A (zh) * 2019-01-07 2019-04-16 中国科学院过程工程研究所 一种从Cohn组分Ⅴ上清中分离纯化人血清白蛋白的方法

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